Amyloidosis is not a single disease entity but rather a diverse group of progressive disease processes characterized by extracellular tissue deposits of a waxy, starch-like protein called amyloid, which accumulates in one or more organs or body systems. As the amyloid deposits accumulate, they begin to interfere with the normal function of the organ or body system. There are at least 15 different types of amyloidosis. The major forms are primary amyloidosis without known antecedent, secondary amyloidosis following some other condition, and hereditary amyloidosis.
Many diseases of aging are based on or associated with amyloid-like proteins and are characterized, in part, by the buildup of extracellular deposits of amyloid or amyloid-like material that contribute to the pathogenesis, as well as the progression of the disease. These diseases include, but are not limited to, neurological disorders such as Alzheimer's Disease (AD), Lewy body dementia, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type); the Guam Parkinson-Dementia complex. Other diseases which are based on or associated with amyloid-like proteins are progressive supranuclear palsy, multiple sclerosis, Creutzfeld Jacob disease, Parkinson's disease, HIV-related dementia, ALS (amyotropic lateral sclerosis), Adult Onset Diabetes, senile cardiac amyloidosis, endocrine tumors, and others, including macular degeneration.
The polypeptide β-amyloid (Aβ) is likely to play a central role in the pathogenesis of Alzheimer's disease (AD). Vassar et al., J. Neurosci. 29:12787-12794 (2009). Aβ polypeptide accumulation in the CNS results in synaptic dysfunction, axon degeneration and neuronal death. The brains of AD patients show a characteristic pathology of prominent neuropathologic lesions, such as neurofibrillary tangles (NFTs), and amyloid-rich senile plaques. The major component of amyloid plaques is Aβ. These lesions are associated with massive loss of populations of central nervous system (CNS) neurons and their progression accompanies the clinical dementia associated with AD.
Aβ is the proteolytic product of the precursor protein, beta amyloid precursor protein (β-APP or APP). APP is a type-I trans-membrane protein which is sequentially cleaved by two proteases, a β- and γ-secretase. The β-secretase, known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), first cleaves APP to expose the N-terminus of Aβ, thereby producing a membrane bound fragment known as C99. Vassar et al., J. Neurosci., 29:12787-12794 (2009) and UniProtKB/Swiss-Prot Entry P56817 (BACE1_HUMAN). The γ-secretase then is able to cleave C99 to produce the mature Aβ polypeptide. Aβ is produced with heterogenous C termini ranging in length from 38 amino acids to 43 amino acids. The 42 amino acid form of Aβ (Aβ42) is the fibrillogenic form of Aβ and is over produced in patients with Down's syndrome and has been suggested to play a role in the early pathogenesis of AD. Vassar et al., J. Neurosci. 29:12787-12794 (2009). BACE1 has thus become a therapeutic target as its inhibition would presumably inhibit Aβ production.
Indeed, BACE1 knock-out mice (BACE1−/−) do not produce cerebral Aβ, confirming that BACE1 is the major, if not only, enzyme responsible for producing Aβ in the brain. Roberds et al., Human Mol. Genetics 10:1317-1324 (2001). Moreover, BACE1 knockout mice in AD models do not form amyloid plaques; cognitive defects and cholinergic dysfunction are rescued as well. McConlogue et al., J. Biol. Chem. 282: 26326-26334 (2007); Ohno et al., Neuron 41: 27-33 (2004); and Laird et al., J. Neurosci. 25:11693-11709 (2005). Additionally, BACE1 heterozygous knock-out mice have reduced plaque formation indicating the complete inhibition of BACE1 activity is not necessary for plaque reduction. McConlogue et al., J. Biol. Chem. 282: 26326-26334 (2007).
The discovery of BACE-1 (Hussain, I. et al. (1999) Mol Cell Neurosci 14: 419-27; Sinha, S. et al. (1999) Nature 402: 537-40; Vassar, R. et al. (1999) Science 286: 735-41; Yan, R. et al. (1999) Nature 402: 533-7; Link, X. et al. (2000) Proc Natl Acad Sci USA 97: 1456-60), along with its structure in complex with a substrate-like peptidomimetic inhibitor OM99-2 (Hong, L. et al. (2000) Science 290: 150-3) initiated the recent era of pharmaceutical development, triggering the development of many types of BACE1 inhibitors. The first waves of inhibitors were small molecule peptidomimetics (Luo, X. et al. Int J Clin Exp Pathol 3: 618-28), which have yet to show clinical success, due in part to the challenge of penetrating the blood brain barrier (BBB). Subsequently, many fragment-based and non-peptidic approaches have led to compounds more suitable for delivery across the BBB to the central nervous system (CNS) (Silvestri, R. (2009) Med Res Rev 29: 295-338; Luo, X. et al. (2010) Int J Clin Exp Pathol 3: 618-28). Most recently, the development of antibodies has emerged (Pul, R. et al. (2011) Expert Opin Biol Ther 11: 343-57). The first class targets Aβ and clears it from the circulation, acting as a sink to modulate Aβ levels in the CNS. The newest class of antibodies targets BACE1 itself, by binding to an exosite and acts as a noncompetitive inhibitor (Atwal, J. K. et al. (2011) Sci Transl Med 3: 84ra43; Zhou, L. et al. (2010) J. Biol. Chem. 286: 8677-8687). In mice and cynomolgus monkeys, anti-BACE1 reduces not only peripheral Aβ levels, but surprisingly those in the cerebrospinal fluid (CSF) as well. Further engineering of this antibody to incorporate receptor mediated transcytosis across the BBB via bispecific anti-BACE1 anti-transferrin antibodies has resulted in even more effective pharmacodynamic reduction of Aβ in the CNS (Yu, Y. J. et al. (2011) Sci Transl Med 3: 84ra44).
It would be beneficial to have an effective therapeutic inhibitor of BACE1 to reduce Aβ production in patients with neurological diseases and disorders, such as AD. The invention provided herein relates to such inhibitors, including their use in a variety of methods.
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.